Good News and Bad News
Authors: P. Muntner, A. Menke, Salvo K. De, F. Rabito, V. Batuman
Journal: Journal of the American Society of Nephrology (2006)

Lead intoxication has been known for millennia. For instance, it had been postulated that lead poisoning due to the high lead concentration in Roman wines contributed to the downfall of the Roman empire (1) or the terminal illness of Herodes (2). In the 19th century, a high prevalence of occupational lead intoxication had been well documented (3) in addition to its association with renal disease in patients with symptomatic lead intoxication (4,5), which was also investigated in greater detail more recently (6). Meanwhile, symptomatic occupational lead intoxication has virtually disappeared, but asymptomatic, subclinical occupational or environmental lead intoxication is still encountered (7,8): occupational exposure (e.g., in painters and plumbers), environmental exposure (e.g., from remains of ancient mining with contamination of soil, dust in old homes, contamination of soil by leaded fuel), or other types of exposure such as leakage from lead-containing vessels or dishware (9), herbal medicine (10), or leaded paint. Of more general concern may be the fact that the environmental lead burden has generally increased. This has been documented by studying Greenland ice, the lead content of which rose in 800 BC with the beginning of silver mining, rising further in the 18th century with the beginning of the industrial revolution, and rising dramatically after 1940 after the widespread introduction of leaded gasoline (11). This finding is paralleled by the observation that skeletal lead content is considerably increased in contemporaneous bone samples compared with prehistorical samples, e.g., ancient Peruvians (12). There has been considerable concern about the effects of low level lead exposure and particularly the neurodevelopmental sequelae of childhood lead exposure (13). Less spectacular, but of definite relevance to the nephrologist, are the potential sequelae of low-level lead exposure on renal function and BP (14,15). It had been shown experimentally that lead causes progressive tubular atrophy and interstitial fibrosis (16), overexpression of angiotensin II (17), generation of oxidative stress (18), as well as salt retention, hypervolemia, and hypertension (19). A number of cross-sectional or retrospective studies had also found that the age-related decline in renal function of the general population correlated with blood lead levels (20–22), although the retrospective design and the incomplete adjustment for confounders limit the validity of these studies. It had also been noted that low-level environmental lead exposure is associated with more rapid progression of renal failure in patients with primary renal disease and no known exposure to lead (23), and the occurrence of gout de novo may be an indicator of a higher lead burden (24). The relation of lead burden to progression was confirmed in a prospective study, which documented that doubling of serum creatinine or end-stage renal disease was seen more frequently in patients with high-normal as opposed to low body lead burden (25) when assessed by the ethylene diaminotetraacetic acid (EDTA) mobilization test (24). The role of lead is made even more convincing by a further study in chronic kidney disease (CKD) patients: In a first observational phase a higher body lead burden was identified as a predictor of the rate of loss of GFR; in a subsequent phase patients with a high-normal body lead burden were randomized to receive at regular intervals placebo or infusions of calcium disodium EDTA. The authors observed improvement of renal function and slower progression in the patients receiving chelate therapy (26). Admittedly, because of the protean biochemical and cellular effects of EDTA, this observation does not definitely prove causality, i.e., that the benefit was the specific result of removal of lead (27), but it is the most compelling evidence we have so far for a role of lead in CKD progression. Nevertheless, the renal community did not pay excessive attention to the potential role of low-level environmental lead exposure as a factor promoting progression. It is against this background that the study of Muntner et al. (28) is a timely reminder. Although environmental exposure to lead has undoubtedly diminished as a result of legal actions banning the use of lead in gasoline, paint, and soldering of cans (29), low-level exposure persists. It is true that the National Health and Nutrition Examination Survey (NHANES) showed a decline in blood lead levels in the US (30), but on the other hand there is no evidence that a safe threshold exists. This consideration prompted the study by Munter and colleagues. The cross-sectional surveys of NHANES III 1988 to 1994 and NHANES 1999 to 2002 were used to obtain measurements of venous whole blood lead concentrations and to measure serum creatinine levels with the modified Jaffe kinetic method calculating eGFR using a simplified MDRD (Modification of Diet in Renal Disease) equation. The good news from a public health perspective is that, between 1988 and 1994 and between 1999 and 2002, the age-standardized geometric mean blood lead level decreased by 41%. This was found in each age group, men and women, and in different ethnicities. The frequency of blood lead levels in excess of 10 μg/dl had declined from 3.3% in 1988 to 1994 to 0.7% in 1999 to 2002. High lead levels were more frequent in the elderly, in men, and in minorities, and were associated after multivariable adjustment with cigarette smoking, alcohol consumption, high school education, and the presence of health insurance. The bad news is that even after appropriate adjustment the prevalence of CKD was progressively higher at higher quartiles of blood lead levels: compared to the first quartile (blood lead < 1.06 μg/dl) with an odds ratio (OR) of 1.0, the OR in the second quartile (1.06 to 1.63 μg/dl) was 1.49, in the third quartile (1.63 to 2.47 μg/dl) it was 1.83, and in the fourth quartile (>2.47 μg/dl) it was 2.72 (P < 0.001). In contrast to previous studies there was no significant association with high BP except in the minorities. Obviously lead exposure continues to be a problem in the low socioeconomic strata of American society. Although blood lead levels are admittedly not the optimal biomarker, more sophisticated measures such as mobilizable lead and bone lead are impractical for such large population studies. Undoubtedly lead has virtually lost its former role as the cause of renal failure. Nevertheless, the present study adds weight to the notion that apparently it is a factor aggravating progression—a role not on the radar screen of most nephrologists.